1. Field of the Invention
This invention relates to sterilized cyanoacrylate adhesive compositions with x-ray imaging capabilities, methods of making such compositions, and methods of using such compositions.
2. Brief Description of Related Technology
In recent years, the use of cyanoacrylate-based biomedical adhesives and sealants has increased dramatically. Once seen as a triage type of treatment, cyanoacrylate-based biomedical adhesives and sealants have found their way into more mainstream use, for instance, as topical wound closure treatments. More recently, internal applications of cyanoacrylate-based biomedical adhesives and sealants have been and are currently being explored.
In such applications, it is desirable for the cyanoacrylate-based biomedical adhesives and sealants to be sterilized against bacterial growth. One commercially successful way to achieve that sterilizing is described and claimed in U.S. Pat. No. 5,530,037 (McDonnell). The '037 patent, under which a product manufactured by Henkel Loctite (Ireland) Ltd. and distributed in the U.S. by Tyco Healthcare under the registered trade mark INDERMIL, provides a curable cyanoacrylate adhesive composition for use in bonding tissue, where the composition has been sterilized in liquid form by gamma irradiation and is the irradiation product of a composition comprising a cyanoacrylate monomer; and a combination of an anionic stabilizer and a free-radical stabilizer in amounts effective to stabilize the composition during irradiation and to stabilize the sterilized composition during storage prior to cure.
Particularly for internal use applications in patients, it would be desirable to observe the location of the cyanoacrylate-based biomedical adhesive and sealant after dispensing onto or into the desired area of the patient. With certain cyanoacrylate-based biomedical adhesives and sealants designed and developed for topical use, a dye has been introduced into the adhesive or sealant composition to assist in visualization on the skin once applied. See for instance HISTOACRYL BLUE from B. Braun Melsungen AG. However, with internal applications, a simple dye cannot be visualized. Instead, a radiopaque material should be employed.
Radiopaque materials have been proposed for use with cyanoacrylates in the past. For instance, U.S. Pat. No. 4,713,235 (Krall) describes and claims radiopaque polymerizable cyanoacrylate compositions that are mixtures of an ester of 2-cyanoacrylic acid and a radiopaque additive stable to and not substantially decreasing the storage life of the cyanoacrylate ester. This additive the '235 patent reports is selected from triiodophenol, iodoform and tetraiodoethylene. The so-formed radiopaque polymerizable cyanoacrylate compositions have between 0.5 and 11 mole percent iodine atoms. These iodo additives have poor solubility in cyanoacrylates generally, however, and thus require heating in order to dissolve them.
Other contrast agents have been used in cyanoacrylates as well. For instance, U.S. Pat. No. 6,562,317 (Greff) describes and claims a composition suitable for treating a solid mass tumor in a mammal. This composition includes a biocompatible prepolymer; an optional biocompatible solvent; and from about 0.1 to about 25 weight percent of a water insoluble radioisotope having from a radioactive content of from about 0.5 microcurie to about 100 millicurie. The biocompatible prepolymer may be cyanoacrylate. Optionally, the composition may include a non-radioactive contrast agent, which may be water soluble or water insoluble. The water-soluble contrast agents are selected from metrizamide, iopamidol, iothalamate sodium, iodomide sodium, and meglumine; the water-insoluble contrast agents are selected from tantalum, tantalum oxide, barium sulfate, tungsten, gold and platinum.
And U.S. Pat. No. 6,759,028 (Wallace) describes and claims a method for treating an arteriovenous malformation (“AVM”) in a mammal. This method includes the steps of selecting a fluidic composition comprising a biocompatible prepolymer, a water insoluble radioisotope and optionally a biocompatible solvent; and injecting a sufficient amount of the composition into one of more vascular sites leading to or within the AVM under conditions, where a solid mass is formed thereby ablating at least part of the then AVM, where the radioisotope is employed in an amount effective to further ablate the AVM and to inhibit regrowth of the AVM. Like the '317 patent above, the composition may be a cyanoacrylate with a contrast agent selected from those recited in the preceding paragraph. U.S. Pat. No. 5,695,480 (Evans) speaks more generally about specific compositions embraced by those used in the methods of the '317 and '028 patents. Water insoluble contrast agents are undesirable because they tend to destabilize cyanoacrylates (causing the cyanoacrylates to prematurely cure) and sediment from the cyanoacrylate composition. Once sedimented, at least with silver contrast agents in thickened cyanoacrylate compositions, the silver contrast agents are difficult to re-disperse.
Also, in the context of treating AVMs, butyl cyanoacrylate has been combined with Lipiodol (iodinized ethyl esters of poppy seed oil fatty acids) and tantalum. However, Liopodol destabilizes the butyl cyanoacrylate, and as such the components must be mixed immediately prior to use. Thus, such Lipiodol/tantulum-containing cyanoacrylate compositions do not have a shelf life, and cannot reasonably be made to be a practical commercial product in a one part composition.
In A. Artola et al., “A Radiopaque Polymeric Matrix for Acrylic Bone Cement”, J. Biomaterial Res. Part B; Appl. Biomaterial 64B, 44-55 (2002), the authors refer to the use of a radiopaque agent, 4-iodophenol methacrylate, in a bone cement for implants that consisted of methyl methacrylate as the resin matrix. In their conclusions, the authors note that cements containing 15% 4-iodophenol methacrylate performed better as a bone cement than conventional cements containing barium sulfate as an x-ray contrast agent.
Despite the state of the technology, there has been no disclosure, teaching, suggestion or motivation to date to use 4-iodophenol methacrylate (or any iodophenol-substituted methacrylate) in a matrix other than methacrylates for use as anything other than bone cements. Thus, because of the state of the technology, there was no disclosure, teaching, suggestion or motivation to date to use iodophenol-substituted methacrylates in a cyanoacrylate composition, let alone one that has been sterilized and whose end use is suitable for use as adhesives and sealants with soft tissue.